Persistent high-risk human papillomavirus (HPV) infection, like that of HPV16, is linked to the development of cervical and several other cancers. The HPV family of viruses establishes persistent infections because it has evolved mechanisms that allow it to evade the human immune system. The long-term goal of this study is to understand how HPV evades the immune system in order to find new ways to treat HPV infection and associated diseases. One of the potential mechanisms by which HPV escapes immunity is inducing tolerance via antigen presentation in the absence of co-stimulation by Langerhans cells (LC), the antigen-presenting cells at the site of HPV infections. Preliminary data shown here suggest that the L2 minor capsid protein may mediate immune escape by interacting with a specific receptor on LC thereby suppressing the maturation of LC and that it may be possible to activate HPV-exposed LC with Toll-like receptor (TLR) agonists. However it is unknown whether these TLR agonists will be potent enough to overcome the suppressive effects of HPV-exposed LC on T cells and induce HPV-specific T cell responses. We hypothesize that: 1) To escape T cell immunity, HPV16 L2 suppresses the maturation of LC through interaction with the cell surface receptor ANXA2; and 2) The use of immune-modulating compounds will enable reversal of the immune-suppressive phenotype and function of HPV-exposed LC from cervical intraepithelial neoplasia (CIN) patients, and induce activation of HPV-specific T cells. To address these hypotheses, the following aims will be explored: Aim 1) Determine whether HPV16 L2 is responsible for suppressing the maturation of LC through interaction with ANXA2. Aim 2) Determine whether HPV16-exposed LC tolerize T cells. Aim 3) Investigate whether immune-modulating compounds can reverse the immune- suppressive phenotype and function of HPV16-exposed LC from CIN patients. Aim 4) Determine whether, apart from HPV16, other high-risk, low-risk and wart type HPV also suppress LC maturation. These aims will be investigated to get a more detailed understanding of how HPV mediates immune escape via interactions with LC and define compounds that have the potential to inhibit or reverse it. In the near future, this mechanistic research could lead to the identification of compounds for testing in clinical trials, with the goal of clearing persistent HPV infection and therefore reducing risk of developing more serious disease such as cervical and other HPV-associated cancers. 1 PUBLIC HEALTH RELEVANCE: Human papillomavirus (HPV) is a significant public health problem because it is wide-spread, persists, causes several diseases, and the preventive vaccine does not eliminate existing HPV infection. Successful completion of this project will lead to an understanding of why the immune system fails to clear HPV infections and the development of strategies to expedite viral clearance in infected women, thereby preventing HPV-induced lesions including cancer.